Cellular Immunity and Immune Escape from EGFR Antibody Therapy

EGFR 抗体治疗的细胞免疫和免疫逃逸

• 批准号: 8322146
• 负责人: ROBERT L FERRIS
• 金额: $ 20.02万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8322146
• 关键词: Animal Model; Antibodies; Antibody Therapy; Apoptosis; Biological; Biological Markers; Biological Models; Cell Communication; Cell Line; Cell model; Cells; Cellular Immunity; Cetuximab; Clinical; Clinical Trials; Cytolysis; Cytotoxic T-Lymphocytes; Data; Defect; Dendritic Cells; Disease; Effector Cell; Enrollment; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Equilibrium; Erbitux; Frequencies; Generations; Genetic Polymorphism; Genotype; Glycocalyx; Head and Neck Squamous Cell Carcinoma; Immune; Immune response; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapy; In Vitro; Institution; Lesion; Lymphocyte; Lytic; Malignant - descriptor; Mediating; Monoclonal Antibodies; Natural Killer Cells; Patient Selection; Patients; Peptides; Peripheral Blood Mononuclear Cell; Regulatory T-Lymphocyte; Sampling; Specialized Program of Research Excellence; T-Lymphocyte; Testing; Tumor Antigens; Tumor Escape; antigen processing; base; clinical application; clinical efficacy; clinically relevant; effective therapy; improved; in vivo; interest; killings; monocyte; neoplastic cell; prospective; receptor; receptor expression; response; therapy design; tumor; uptake

There is convincing clinical evidence that the epidermal growth factor receptor (EGFR)-specific monoclonal antibody (mAb), cetuximab, is effective therapy for advanced head and neck squamous cell carcinoma (SCCHN). However, not all patients respond to cetuximab, and clinical responses are not correlated with level of EGFR expression on tumor cells. Thus, there is a need to understand why clinical responses vary among patients, in order to select those most likely to respond to cetuximab therapy. In contrast to EGFR tyrosine kinase inhibitors, the antitumor activity of cetuximab may benefit from its interactions with host's immune system, since cetuximab induces significant killing of SCCHN cells in vitro only in combination with natural killer (NK) cells and monocytes. Furthermore, in an animal model system the antitumor activity of cetuximab is enhanced by the addition of NK cells. This information has provided the rationale for our hypothesis that the antitumor activity of cetuximab is influenced by its ability to trigger an EGFR-specific cellular immune response and by the escape mechanisms SCCHN cells utilize to avoid immune recognition and destruction. In this proposal, we will first characterize in vitro the variables, which are involved in the generation of EGFR-specific cytotoxic T lymphocytes (CTL) by cetuximab. They include the polymorphism of the Fcy receptors expressed by NK cells, the EGFR expression level on SCCHN cells, and the ability of dendritic cells (DC) to cross-present tumor antigens to T cells following loading with SCCHN cells coated with cetuximab. In addition, we will characterize how the immunosuppressive activity of regulatory T cells interferes with the generation of EGFR-specific CTL as well as with their lytic activity and that of NK cells. To assess the clinical relevance of the in vitro results, we will determine how the balance between the induction of an EGFR-specific CTL response triggered by cetuximab and the immune escape mechanisms utilized by SCCHN cells impacts the clinical response to (antitumor activity of) cetuximab in SCCHN patients who will be enrolled in a trial associated with this project. The results derived from this study will have an impact on the clinical application of cetuximab-based immunotherapy in SCCHN patients by identifying predictive immune biomarkers of biological and clinical responses, optimizing the selection of patients to be treated with cetuximabbased immunotherapy and contributing to the design of interventions to enhance its efficacy. Furthermore, the principles defined with cetuximab may be applicable to other TA-specific mAb; therefore, the information derived from this translational proposal may have a broad significance for the clinical application of antibody-based immunotherapy to the treatment of malignant diseases.

有令人信服的临床证据表明，表皮生长因子受体（EGFR）特异性单克隆抗体（mAb），西妥昔单抗，是晚期头颈部鳞状细胞癌（SCCHN）的有效治疗。然而，并非所有患者都对西妥昔单抗有反应，临床反应与肿瘤细胞上EGFR表达水平无关。因此，有必要了解为什么临床反应在患者之间存在差异，以便选择最有可能对西妥昔单抗治疗有反应的患者。与EGFR酪氨酸激酶抑制剂相比，西妥昔单抗的抗肿瘤活性可能受益于其与宿主免疫系统的相互作用，因为西妥昔单抗仅在与自然杀伤（NK）细胞和单核细胞组合时才在体外诱导显著的SCCHN细胞杀伤。此外，在动物模型系统中，西妥昔单抗的抗肿瘤活性通过添加NK细胞而增强。这些信息为我们的假设提供了依据，即西妥昔单抗的抗肿瘤活性受到其触发EGFR特异性细胞免疫应答的能力以及SCCHN细胞用于避免免疫识别和破坏的逃逸机制的影响。在这个建议中，我们将首先在体外的变量，这是参与生成EGFR特异性细胞毒性T淋巴细胞（CTL）的西妥昔单抗的特点。它们包括NK细胞表达的Fc γ受体的多态性，SCCHN细胞上的EGFR表达水平，以及树突状细胞（DC）在负载西妥昔单抗包被的SCCHN细胞后向T细胞交叉呈递肿瘤抗原的能力。此外，我们还将描述 调节性T细胞干扰EGFR特异性CTL的产生以及它们的裂解活性和NK细胞的裂解活性。为了评估体外结果的临床相关性，我们将确定西妥昔单抗引发的EGFR特异性CTL应答诱导与SCCHN细胞利用的免疫逃逸机制之间的平衡如何影响将入组本项目相关试验的SCCHN患者对西妥昔单抗（抗肿瘤活性）的临床应答。本研究的结果将通过鉴定生物学和临床反应的预测性免疫生物标志物，优化西妥昔单抗免疫治疗患者的选择，并有助于设计干预措施以增强其疗效，从而对SCCHN患者中基于西妥昔单抗的免疫治疗的临床应用产生影响。此外，西妥昔单抗定义的原则可能适用于其他TA特异性mAb;因此，从该翻译提案中获得的信息可能对基于抗体的免疫治疗在恶性疾病治疗中的临床应用具有广泛意义。